Temporal Trends in the Outcomes of Percutaneous Coronary Intervention With Zotarolimus Eluting Stents Versus Everolimus Eluting Stents: A Meta‐Analysis of Randomized Controlled Trials

ABSTRACT Introduction Long‐term follow‐up results of various trials comparing Zotarolimus eluting stents (ZES) with Everolimus eluting stents (EES) have been published recently. Additionally, over the last decade, there have been new trials comparing the ZES with various commercially available EES. We aim to conduct an updated meta‐analysis in light of new evidence from randomized controlled trials (RCTs) to provide comprehensive evidence regarding the temporal trends in the clinical outcomes. Methods A comprehensive literature search was conducted across PubMed, Cochrane, and Embase. RCTs comparing ZES with EES for short (<2 years), intermediate (2–3 years), and long‐term follow‐ups (3–5 years) were included. Relative risk was used to pool the dichotomous outcomes using the random effects model employing the inverse variance method. All statistical analysis was conducted using Revman 5.4. Results A total of 18 studies reporting data at different follow‐ups for nine trials (n = 14319) were included. At short‐term follow‐up (<2 years), there were no significant differences between the two types of stents (all‐cause death, cardiac death, Major adverse cardiovascular events (MACE), target vessel myocardial infarction, definite or probable stent thrombosis or safety outcomes (target vessel revascularization, target lesion revascularization, target vessel failure, target lesion failure). At intermediate follow‐up (2–3 years), EES was superior to ZES for reducing target lesion revascularization (RR = 1.28, 95% CI = 1.05–1.58, p < 0.05). At long‐term follow‐up (3–5 years), there were no significant differences between the two groups for any of the pooled outcomes (p > 0.05). Conclusion ZES and EES have similar safety and efficacy at short, intermediate, and long‐term follow‐ups.


| Introduction
Drug-eluting stents (DES) have changed the paradigm of percutaneous coronary interventions ever since the harsh learnings from Bare Metal Stent (BMS) Era in the late 1990s [1][2][3].Improvements in stent design have resulted in clinically improved outcomes albeit at the expense of stent thrombosis (ST) or very late ST as in the case of BMS and first-generation DES [3][4][5].However, the knowledge of the persistence of adverse events with both first-generation and contemporary DES presents an opportunity for improvement [6].Specifically, dedicated longitudinal follow-up in clinical trials offers greater insight into the effectiveness of DES, and the accrual of events may amplify the ability to distinguish outcomes between therapies [7].As an example, it was long-term surveillance of first-generation DES that introduced the risk associated with late ST, and detailed patient-level observation for years beyond a trial's primary endpoint [4].This has now become a regulatory mandate.Detailed ascertainment of events permits insight into not only annualized estimates of stent thrombosis but also the persistence of late target lesion revascularization that seems constant with existing DES.
Coronary interventions cause endothelial disruption and vascular injury that leads to the initiation of healing processes through mitogen-mediated proliferation of vascular smooth muscle cells (VSMC) and migration of these smooth muscle cells from the media to the intima [8].Currently, available anti-restenotic drugs primarily target this which is the key event for the formation of neointimal hyperplasia and restenosis [8,9].First-generation DES and second-generation DES differ in the drug used to achieve this anti-restenotic effect which can attributed to differences in drug solubility and mean tissue concentration [10,11].These drugs also differ in terms of structure, molecular weight, potency, and lipophilicity.Zotarolimus and Everolimus are sirolimus analogs that have a lipophilic tetrazole and hydroxyethyl group instead of the hydroxyl group at position 40 of the sirolimus, respectively [12,13].Zotarolimus is a highly lipophilic analog of sirolimus and was designed for vascular injury [14].Everolimus has a much higher interaction with the mechanistic target of rapamycin complex 2, higher bioavailability, and shorter half-life than sirolimus and has shown more rapid endothelization [15].
With regard to the Everolimus eluting stents (EES) group, there also exists a considerable range of differences in drug concentration, complete drug elution time, polymer coating (durable, bioabsorbable), stent platform, strut shape (round or square) links/connectors and finally, its composite thickness and that of the stent and the polymer [16,17].The BioLink polymer in R-Zotarolimus eluting stents (ZES), which is made up of three polymers-a hydrophobic C10 polymer, a hydrophilic C19 polymer, and water-soluble polyvinyl pyrrolidinone-and the two-layer polymer system in EES, which has an acrylate primer and a fluorinated copolymer, both release antiproliferative agents from biocompatible durable polymers [9,13].
Data regarding the safety and efficacy of both stent types is limited.Previous meta-analyses did not assess clinical outcomes beyond the 2-3-year follow-up or were limited in the number of pooled studies [18,19].Only recently we have had access to 5-year follow-up data [7,20].There is no headto-head comparison of Resolute-ZES (Medtronic) and the composite of all different commercially available stents with EES as well.Considering this literature gap, we conducted the present study that has systematically synthesized evidence regarding the safety and efficacy of ZES compared with EES on short-, intermediate-, and long-term follow-ups.Our metaanalysis comprises all comers PCI using ZES/EES including acute coronary syndromes, left ventricular dysfunction, diabetes mellitus, and small vessels.

| Methods
This systematic review and meta-analysis was conducted following the guidelines established by Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) [21] and the Cochrane Handbook of Systematic Reviews [22].

| Data Sources and Search Strategy
Two authors (A.A. and M.A.) independently searched PubMed/ MEDLINE, Scopus, Embase, the Cochrane Library, and ClinicalTrials.govfrom their inception till October 1, 2023.No language restrictions were applied.The aim was to identify all randomized controlled trials (RCTs) and their follow-up reports that aimed to assess the safety and efficacy of ZES compared with EES.The researchers screened references from retrieved trials, previous meta-analyses, and review articles to identify all studies that fulfill the eligibility criteria.The detailed search strategy for three databases is provided in Supporting Information S1: Table 1.
The studies were eligible for inclusion in our systematic review and meta-analysis if they were: (i) RCTs (ii) Short (<2 years), Intermediate (2-3 years), or long-term (3-5 years) follow-up reports of RCTs; (iii) RCTs that included adult male or female patients who were >18 years old; (iv) compared clinical outcomes of ZES with EES; (v) assessed at least one of the predetermined clinical outcomes.In the case of trials reporting outcomes at two different intervals for the same follow-up strata (e.g., for long-term follow-up, if outcomes were separately reported for 4-and 5-year follow-up, the data was extracted and pooled for longer follow-up).Post hoc analyses of parent RCTs were excluded.The detailed inclusion and exclusion criteria of our meta-analysis are given in Supporting Information S1: Table 2.
The primary outcome was safety assessed in terms of all-cause death, cardiac death, major adverse cardiovascular events (MACE), target vessel myocardial infarction (MI), definite or probable stent thrombosis (ST), and definite ST while the secondary outcome was efficacy gauged in terms of target vessel revascularization (TVR), target lesion revascularization (TLR), target vessel failure (TVF), and target lesion failure (TLF).The detailed definitions of included outcomes are given in Supporting Information S1: Table 3.All outcomes were assessed on short (<2 years), intermediate (2-3 years), and long-term (3-5 years) follow-ups.

| Study Selection, Data Extraction, and Quality Assessment
The studies identified from the literature search were imported to EndNote X9 (Clarivate Analytics), and duplicate records were removed.Two researchers (A.A. and M.A.) independently reviewed the studies based on their titles and abstracts.This was followed by a review of the full-text of the studies, and any study that fulfilled our predetermined eligibility criteria was included.A third author (J.B.) was consulted in case of any disagreement.
We extracted the following data from each study: author surname, publication year, number of patients in ZES and EES groups, mean age of patients, percentage of males among the study participants, details of patient population, intervention subtype, use of dual antiplatelet therapy, duration of follow-up, and primary and secondary outcomes.
The Cochrane risk of bias tool (RoB 2.0) was used for assessing the risk of bias for the included RCTs [23].The risk of bias was assessed across the following domains: randomization, deviations from intended variation, missing outcome data, measurement of outcome, and selection of reported results.The trials were scored based on a high, some concerns, or low risk of bias in each domain.Traffic light plots were created using the Robvis tool [24].

| Statistical Analysis
RevMan Version 5.4 (Nordic Cochrane Center, Copenhagen, Denmark) was used for data analysis.We used risk ratio (RR) along with 95% confidence intervals (CIs) to present results.DerSimonian and Laird random effects model was used to pool results [25] and forest plots were generated to visualize the results.Higgins I 2 test was used to assess heterogeneity across the included studies; low heterogeneity indicated by a value of <25%; moderate heterogeneity indicated by 25%-75%; and >75% indicated high heterogeneity [26].Begg's rank test [27] and Egger's regression test [28] were conducted to assess the risk of publication bias.A p-value of <0.05 was considered significant in all cases.

| Results
We conducted a systematic literature search using PubMed/ Medline, Embase, and Cochrane Library that yielded X records.Duplicate studies were removed, and screening of articles was performed based on title, abstract, and full text.After screening, 18 studies were found eligible to be included in our metaanalysis.The study selection process is shown in Supporting Information S1: Figure 1.The detailed reasons for the exclusion of different RCTs during full-length screening are given in Supporting Information S1: Table 4.

| Quality Assessment and Publication Bias in Included Trials
Most of the RCTs were found to be at low risk of bias while two had high risk of bias.The details of the bias assessment for each trial are given in Supporting Information S1: Figure 2. The publication bias was assessed for 30 pooled outcomes.None of the pooled outcomes showed significant publication bias except TLR at long-term follow-up.The detailed results the Begg's rank and Egger's regression test for each outcome are given in Supporting Information S1: Tables 6-8.The funnel plots for allcause death, cardiac death, and MACE are given in Supporting Information S1: Figure 3.

| Clinical Outcomes on Short-Term
Follow-Up (<2 years) 3.2.1.1 | All-Cause Death.Data for all-cause death was provided by eight studies for the ZES group (events, 131; total, 5861) and the EES group (events, 166; total, 7114).Our pooled analysis showed that there was no significant difference between both groups for reduced risk of all-cause death on short-term follow-up (RR = 0.95, 95% CI: 0.72 to 1.24, p = 0.69 Figure 1A).Low heterogeneity was observed among the included studies for this outcome (I 2 = 20%).

| Cardiac
Death.Our pooled analysis of seven studies providing data for cardiac deaths in the ZES group (events, 80; total, 5537) and EES group (events, 89; total, 6788) demonstrated that the risk of cardiac death was comparable in both groups with no heterogeneity observed across the included studies (RR = 1.08, 95% CI: 0.79 to 1.47, p = 0.62, I 2 = 0% Figure 1B).

| MACE.
Out of 18 eligible studies, data for MACE on short-term follow-up was provided by six studies for ZES group (events, 374; total, 4285) and EES group (events, 320; total, 4285).No significant difference was observed between ZES and EES for MACE (RR = 1.21,

| Definite ST.
Only two studies reported incidence of short-term definite ST in the ZES group (events, 12; total, 2051) and the EES group (events, 7; total, 2047).On pooling the available data, the risk of definite ST was comparable across both groups with a moderate risk of heterogeneity (RR = 1.57, 95% CI: 0.40 to 6.12, p = 0.51, I 2 = 47%, Supporting Information S1: Figure 4C).

| TLR.
The incidence of TLR on short-term followup was provided by eight studies for the ZES group (events, 211; total, 5861) and the EES group (events, 174; total, 7114).On pooling the reported data, no significant difference was found between both groups for this outcome.Heterogeneity was moderate for short-term TLR across the pooled studies (RR = 1.29, 95% CI: 0.99 to 1.68, p = 0.06, I 2 = 38%, Supporting Information S1: Figure 5B).

| Discussion
Our meta-analysis is a direct head-to-head comparison between ZES and EES with outcomes reported over varying follow-up periods.A total of 18 reports consisting of data from 9 trials and over 3 follow-ups were included.The pooled analysis showed that throughout the three distinct follow-up periods-short (<2 years), intermediate (3-5 years), and long (>5 years), ZES and EES had a similar safety profile with comparable results for all-cause death, cardiac death, MACE, target vessel MI, and stent thrombosis.The efficacy of the two DES was also comparable with no significant differences for TVR, TVF, and TLF.However, on intermediate follow-up, there was a significantly reduced risk of TLR in the EES group but no significant differences were observed in TLR at short and long follow-up.
Similar findings were demonstrated in a previously published meta-analysis that pooled five studies [18]  More than 80% of PCI patients receive DES, which is the accepted standard of treatment in modern clinical practice [45].
Recent advancements in stent design, comparable or greater anti-restenotic effectiveness, and steadily declining incidence of late ST have led to the replacement of old-generation DES with new-generation DES especially after 1 year [46,47].Therefore, other considerations, such as cost-effectiveness, may play us guide preference.
One study [48] concluded that EES seems to be a cost-effective treatment for patients with ST-segment elevated myocardial infarction because of its incremental efficacy, even if its overall costs were greater than those of BMS.The estimated incremental cost-effectiveness ratios were below the generally acceptable threshold values.Whereas another study [49] demonstrated that when it came to cost-reduction, second-generation DES (Zotarolimus and Everolimus) was superior to BMS (saving €184 with the base case).This was mostly because there were fewer second revascularizations, no myocardial infarctions, and no stent thrombosis.However, since ZES and EES's cost efficiency has not been directly compared before, it is the area that should be the focus of future research.The studies comparing the efficacy of drug-eluting stents have shown contrasting results.A metashowed superiority of everolimus-eluting stents as they significantly reduced the risk of repeat revascularisation and definite stent thrombosis compared to sirolimus-eluting stents [50].However, the results were mainly based on short follow-up parent RCTs without pooling the long-term follow-up data.
Another study [18] showed comparable clinical outcomes with everolimus-eluting stents and zotarolimus-eluting stents.However, the investigators pooled only five RCTs and reported data at short-term follow-up.In contrast to the previously available reviews, we pooled 18 studies reporting data for 9 parent RCTs and comprehensively assessed clinical outcomes at 3 different follow-up intervals short (<2 years), intermediate (2-3 years), and long-term periods (3-5 years).This makes our meta-analysis the first review to show comparable efficacy of everolimuseluting stents and zotarolimus-eluting stents on three different follow-up intervals along with pooling data from studies that had not been evaluated in previous analyses.We analyzed only these stent types as several studies had reported their data at different follow-ups.However, it had not been assessed statistically in a direct head-to-head comparison across three follow-up intervals.
Although meta-analyses have been conducted in the past on this topic, our meta-analysis offers a more holistic and updated view regarding the safety and efficacy of ZES compared with EES.We have comprehensively synthesized evidence by pooling recently published studies that had never been pooled in earlier meta-analyses.Robust and meticulous data extraction from multiple studies across variable follow-up intervals has enhanced our meta-analysis statistical power, offering a better understanding of the temporal dynamics of ZES and EES.These temporal trends help evaluate the safety of stents across different follow-ups.Our meta-analysis has accurately assessed the current state of the literature regarding ZES versus EES on short-, intermediate-, and long-term follow-ups.Long-term surveillance of ZES and EES in our study can help clinicians in future decision-making regarding stent usage during PCI.
This study also has some limitations.First, this is a study-level meta-analysis, and the absence of patient-level information made it challenging to evaluate potential effect modifiers.Another potential limitation of this research might be the inclusion of patients who had non-resorbable polymer EES implants, which are older than the present-day EES that employ resorbable polymer and are currently in use.It is important to mention that the differences in lesion complexity and duration of DAPT can also influence results.The post hoc analysis of RCTs will help us better understand the clinical outcomes in patients with complex lesions.Moreover, we observed risk of publication bias

FIGURE 1 |
FIGURE 1 | Forest plots for pooled (A) all-cause death, (B) cardiac death, and (C) MACE on Short-term follow-up.MACE, major adverse cardiovascular events.

FIGURE 2 |
FIGURE 2 | Forest plots for pooled (A) all-cause death, (B) cardiac death, and (C) MACE on Intermediate follow-up.MACE, major adverse cardiovascular events.

FIGURE 3 |
FIGURE 3 | Forest plots for pooled (A) all-cause death, (B) cardiac death, and (C) MACE on Long-term follow-up.MACE, Major adverse cardiovascular events.

FIGURE 4 |
FIGURE 4  | Central illustration summarizing the findings of our meta-analysis.

TABLE 1 |
Baseline characteristics of included studies and participants.
Gu et al. in 2015 2015.5.This study found no significant difference in relative risk when powered for TVR and ST between the two groups.Additionally, another meta-analysis[19]byGu et al. in 2015separately pooled the data from RCTs as well as observational studies.The results of that study revealed that in RCTs, EES and ZES showed comparable safety (MACE, all-cause mortality, nonfatal MI, ST) and efficacy (TVR, TVF, TLF), while in observational studies, EES was safer and more efficacious than ZES in terms of MACE, ST, TVR, TLR, and TLF.Whereas the pooled RCT and observational studies results indicated that EES was safer and more effective than ZES, with a lower risk of MACE, stent thrombosis, TVR, TLR, and TLF.Consequently, these conflicting findings and limited clinical follow-up warranted the need for a comprehensive analysis based on larger clinical trials with various follow-ups to increase the power of the pooled analysis.Our efforts in this meta-analysis purport the above evidence by demonstrating no difference in all causes of death, MACE, TLR, TVF, TVMI, definite/probable ST, and definite ST in short, intermediate, and long-term follow-up except for less TLR with EES as compared to ZES at intermediate follow up.We achieved this by including all comers receiving PCI with ZES/EES.TLR was noted to favor EES over ZES at intermediate-term follow-up but not at longterm follow-up.However, TLF, definite or probable ST, ST, or TVF did not differ at any follow-up interval.It is difficult to ascertain the reasons for such a difference in effect shown at the intermediate follow-up period.